Thiocarbonylthioacetyl cephalosporins

ABSTRACT

Thiocarbonylthioacetylcephalosporins of the general formula   WHEREIN R is hydrogen, lower alkyl, aralkyl, tri(lower alkyl)silyl, a salt forming ion, or the group   R1 is hydrogen, lower alkyl, aralkyl, aryl or certain heterocyclic groups; R2 is a salt forming ion, lower alkyl, aryl or aralkyl; R3 is lower alkyl, aryl or aralkyl; and X is hydrogen, hydroxy, lower alkanoyloxy, aroyloxy, aralkanoyloxy, the radical of a nitrogen base, a quaternary ammonium radical, or together X and R represent a bond linking carbon and oxygen in a lactone ring; are useful as antibacterial agents.

United States Patent Treuner Apr. 29, 1975 THlOCARBONYLTl-IIOACETYL Primary ExaminerNicholas S. Rizzo CEPHALOSPORINS Attorney, Agent, or Firm-Lawrence S. Levinson;

Merle J. Smith [75] Inventor: Uwe D. Treuner, Regensburg,

Germany 571 7 ABSTRACT [73] Assignee: E. R. Squibb 8L Sons, Inc., New Thiocarbonylthioacetylcephalosporins of the general York, NY. formula RCH CO NH--CHCH CH S-C-O-R N CH X ll 2 c c 2 I S C-OR [22] Filed: Mar. 11, 1971 wherein R is hydrogen, lower alkyl, aralkyl, tri(lower alkyl)-silyl, a salt forming ion, or the group [21] Appl. No.: 123,408

CH O C R [52] US. Cl. 260/243 C; 424/246 [51] Int. Cl C0711 99/24 R is hydrogen, lower alkyl, aralkyl, aryl or certain [58] Field of Search 260/243 C h t roc clic groups; R is a salt forming ion, lower alkyl, aryl or aralkyl; R is lower alkyl, aryl or aralkyl; TEE; aiilliili lfil 355113133? i'fiill 'fi @512; UNITED STATES PATENTS quaternary ammonium radical, or together X and R 3,534,029 10/1970 Beycrman C represent a bond carbon and oxygen in a lac- 3,574,190 4/197] Honlmnen ct al. 260/239.l tone ring; are useful as antibacterial agents 3,575,969 4/l97l Morin et al. 260/243 C 3,579,506 5/1971 Lemicux et al. 260/243 C 11 Claims, No Drawings THIOCARBONYLTHIOACETYL CEPHALOSPORINS SUMMARY OF THE INVENTION 1 CH co NH l S-C-O-R R represents hydrogen, lower alkyl, aralkyl, tri- (lower alkyl) siiyl, a salt forming ion or the group especially hydrogen, methyl, pivaloyloxy, sodium or potassium; R is phenyl, thienyl, furyl, oxazolyl, isoxazolyl or thiazolyl, especially phenyl, R is lower alkyl, especially methyl or ethyl; R is lower alkyl, preferably methyl or t-butyl; and X is preferably hydrogen or acetoxy.

DETAILED DESCRIPTION-OF THE INVENTION The various groups represented by the symbols have the meanings defined below and these definitions are retained throughout this specification.

The lower alkyl groups are straight or branched chain hydrocarbon radicals having I to 8 carbons in the chain, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl or the like.

The aryl groups are monocyclic carbocyclic aryl groups including simply substituted members. By way of illustration, this includes the phenyl ring and simply substituted phenyl containing one to three substituents (preferably only one) such as the halogens (chlorine and bromine being preferred), lower alkyl groups such as those defined above, lower alkoxy groups, (i.e., lower alkyl groups of the type defined above attached to an oxygen), hydroxy, carboxy and the like. In the case of the last two named substituents there is preferably only one, especially in the para position of the phenyl. Illustrative are phenyl, mand p-chlorophenyl,

0-, mand p-bromophenyl, 3,4-dichlorophenyl, 3,5- dibromophenyl, 0-, mand p-tolyl, p-methoxyphenyl, 3,4,5-trimethoxyphenyl, p-hydroxyphenyl, p-

carboxyphenyl and the like.

The aralkyl groups include a monocyclic carbocyclic aryl group attached to a lower alkyl group, both as defined above. lllustrative are benzyl, o-, mor p- C-CH -X chlorobenzyl, 0-, mor p-bromobenzyl, o-, mor pmethylbenzyl, phenethyl, p-chlorophenethyl. 3,5- diethylbenzyl, 3,4,5-trichlorobenzyl and the like.

The lower alkanoyloxy, aroyloxy and aralkanoyloxy groups represented by X include the acyl group of acid esters. The lower alkanoyl radicals are the acyl radicals of lower fatty acids containing alkyl radicals of the type described above. The lower alkanoyloxy groups include, for example, acetoxy, propionyloxy, butyryloxy and the like. The aroyloxy groups are derived from monocyclic carbocyclic aryl groups of the kind described. Similarly the aralkanoyloxy groups consist of monocyclic carbocyclic aryl and alkanoyloxy radicals of the type described. X also represents the radical of an amine, e.g., an alkylamine like methylamine, ethylamine, dimethylamine, triethylamine, aralkylamine like dibenzylamine, N,N'-dibenzylpyridinium, pyridinium, l-quinolinium, l-picolinium, etc. X and R may also join together, as indicated above, to form a bond linking carbon and oxygen in a lactone ring.

The heterocyclic groups represented by R are 5- to 6-membered monocyclic heterocyclic radicals (exclusive of hydrogen), including thienyl, furyl, oxazolyl, isoxazolyl and thiazolyl, as well as these heterocyclics with the substituents halo, lower alkyl (particularly methyl and ethyl), lower alkoxy (particularly methoxy and ethoxy) or phenyl.

The salt forming ions represented by R and R may be metal ions, e.g., aluminum, alkali metal ions such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium, or an amine salt ion, of which a number are known for this purpose, for example, dibenzylamine, N,N-dibenzylethylenediamine, methylamine, triethylamine, procaine, N-ethylpiperidine, etc.

The new thiocarbonylthioacetylcephalosporins of this invention are produced by reacting a 7-aminocephalosporanic acid compound of formula II [which includes 7-aminocephalosporanic acid (7-ACA), 7- amino-3-desacetoxycephalosporanic acid (7-ADCA) and other derivatives] of the formula with a thiocarbonylthioacetic acid of the formula (III) R -C3H-COOH S-fiI-O-R or an activated derivative of the former (II). The symbols have the meanings already defined.

The activated derivatives refered to include, for example, the reaction product with an anhydride forming reagent such as ethylchloroformate, benzoyl chloride, pivaloyl chloride, etc., or with bis-imidazolecarbonyl, dicyclohexylcarbodiimide, p-nitrophenol or the like.

The reaction between 7-aminocephalosporanic acid compound and the thiocarbonylthioacetic acid may be effected, for example, by dissolving or suspending the latter in an inert organic solvent such as chloroform, methylene chloride, dioxane, benzene or the like, and adding, at about room temperature or below. about an equimolar amount of an anhydride forming reagent, e.g.. ethyl chloroformate, benzoylchloride or the like, or other activating compound such as dicyclohexylcarbodiimide, along with a salt forming organic base, such as triethylamine, pyridine or the like, followed.

after an interval, by the addition of the 7-aminocephalosporanic acid compound. The product of the reaction is then isolated by conventional procedures, e.g., by concentration or evaporation of the solvent.

When R is the acyloxymethyl group this group may be introduced into the 7-aminocephalosporanic acid moiety prior to the reaction with the thiocarbonylthioacetic acid or the activated derivative by treatment with one to two moles of a halomethyl ester of the formula hal-CH OCOR wherein hal is halogen, preferably chlorine or bromine,

in an inert organic solvent such as dimethylformamide, acetone, dioxane, benzene or the like, at about ambient temperature or below.

As an alternative, a product of formula lmay be produced by reacting a salt, e.g., an alkali metal salt, of the formula or derivative thereof. Me represents a metal, hal is halogen. preferably chlorine or bromine and R and R, are the same as above.

The thiocarbonylthioacetic acid of formula [I] may be produced according to the following general method.

R -CHCOOR (wherein R is hydrogen or lower alkyl) by the procedure of Bonner, Jour. Org. Chem. 33. l83l( l968).

The symbols have the meanings already defined.

, Further process details are also provided in the illustrative examples.

Certain of the compounds of this invention may exist in different optically active forms. The various stereoisomeric forms as well as the racemic mixtures are within the scope of the invention.

The compounds of this invention have a broad spectrum of antibacterial activity against both gram positive and gram negative organisms such as Staphylococcus aureus, Salmonella schotlmuelleri, Pseudomonas aeruginosu, Proteus vulgaris. Escherichia coli and Streptococcus p \'ogenes. They may be used an antibacterial agents in a prophylactic manner, e.g., in cleaning or disinfecting compositions, or otherwise to'combat infections due to organisms such as those named above, and in general may be utilized in a manner similar to cephalothin and other cephalosporins. For example, a compound of formula I or a physiologically acceptable salt thereof may be used in various animal species in an amount of about 1 to 200 mg./kg., daily, orally or parenterally, in single or two to four divided doses to treat infections of bacterial origin, e.g., 5.0 mg./kg. in mice.

Oral forms give prompt high blood levels which are maintained for relatively long periods.

Up to about 600 mg. of a compound of formula I or a physiologically acceptable salt thereof may be incorporated in an oral dosage form such as tablets, capsules or elixirs or in an injectable form in a sterile aqueous vehicle prepared according to conventional pharmaceutical practice.

They may also be used in cleaning or disinfecting compositions, e.g., for cleaning barns or dairy equipment, at a concentration of about 0.01 to 1 percent by weight of such compounds admixed with. suspended or dissolved in conventional inert dry 'or aqueous carriers for application by washing or spraying. They are also useful as nutritional supplements in animal feeds.

The following examples are illustrative of the invention. All temperatures are on the centigrade scale. Additional variations may be produced in the same manner by appropriate substitution in the starting material.

EXAMPLEI To 5.6 gm. mmol.) of DL- [Ethoxythiocarbonyl)thio]-phenylacetic acid [produced by the method of.]. Org. Chem. supra] in ml. of absolute methylene chloride are added 4.12 gm. (20 mmol.) of dicyclohexylcarbodiimide in 20 ml. of methylene chloride and stirred for one half hour at 0 under nitrogen. Then 5.1 gm. of 7-aminocephalosporanic acid trimethylsilyl ester in 10 ml. of methylene chloride are added dropwise and stirred for 12 hours at 05. The reaction mixture is stirred for one more hour at room temperature. This is then filtered with suction under a nitrogen atmosphere to separate the dicyclohexyurea which has formed. The filtrate is evaporated to dryness in vacuo leaving the white amorphous product, the trimethylsilyl ester of DL-7-[2- (ethoxythiocarbonyl)thio]-2-[phenylacetamidolcephalosporanic acid, m.p. (dec.).

Treatment of the ester with water gives the free acid, m.p. 50 (dec.). The beige amorphous potassium salt is obtained by treatment of the free acid with potassium ethylhexanoate solution, m.p. (dec.). The sodium salt is formed similarly.

The following additional products having the formula in the right hand side of the table are obtained by the procedure of Example 1 from starting materials having the formula in the left hand part of the table (the starting materials being obtained by the method of J. Org. Chem. supra):

TABLE 5 R -ca-cooa R CHCONH CHCH ca 1 I l s c O-R I I I 2 fi z 2 c N c-cn x s s f/ C-OR II o Exampl e R1 R2 R:L .R2 5

H 2 H CH CH3 H CH3 3 CH3 c 11 c 3 CH3 c 11 on 4 C31117 C2115 CH3 C l-I CZH5 pyrldlnlum 08 c c H on c H CH ococn 5 a s z 6 5 2 2 HICHs 2 6 5 2 6 5 2 3 u 6 4-c1c a a -cH oc-c a 4-c1c 1r H ococa 7 3,4- (c11 0) c 11 c n c 3 3,4 (ca 0) c r1 c 11 H 0c 8 3,4.5-(CH3O)3C6H2 c 14 c H 3,4,5 (cn o) c n CZHS oc H3 9 4-CH3C6H4 Na Na 4CH3C6H4 Na 'OCOCHEI 10 3.4(Br) C H CH H l actone (+x) 3,4-(Br) C H CH a lactone (+R) OCH 11 2,4-(c1) c a c a c 11 2,4 (c1) c r1 c 11 0c 3 H ococn 12 a s I I 2 5 2 5 C6H5 u 2 5 3 13 c a c 11 c 11 ococa h ll I s 5 I 14 U c a cr1 c 'rr cn j c a ca oocn c a l u 5: 15 c 11 c 11 ca oc-c(ca c 21 c 3 a 6 0 E? (CH c c 00C c H 1 Q 11 0 a c11 -c 3 3 6H5 6H5 6 5 a 17 s s 2 5 H CGHS 2 5 TABLE Cminued Example R R2 R R .R2

1s c a c u Na c a c a 11 I 19 c 3 0 1 1 cH 0-c-c (ca 3 c 11 c 11 ococa C 3 N(c H N(C2H5)3 c rr N(C2H5)3 a 21 CGH5 Na Na C6H5 Na H 22 c 685 Na Na c 11 Na ococa What is claimed is: 2. A compound as in claim 1 wherein R, is phenyl. l. A compound of the formula 3. A compound as in claim 2 wherein R and R each r cu co NH -c1@ cu ca l S-C-O-k o O L wherein R is hydrogen. lower alkyl. R -phenyllower alkyl, tri(lower alkyl)silyl,

or a salt forming ion of the group consisting of aluminum. alkali metal, alkaline earth metal, dibenzylamine. N.N-dibenzylethylenediamine, methylamine. triethylamine. procaine and N-ethylpiperidine, R, is hydrogen, lower alkyl, R,-phenyl-lower alkyl, R,-phenyl, or a monocyclic heterocyclic selected from the group consisting of thienyl, furyl, oxazolyl, isoxazolyl and thiazolyl. and halo, lower alkyl, lower alkoxy or phenyl substituted members of said heterocyclics, R is a salt forming metal of the group consisting of aluminum, alkali metal or alkaline earth metal, lower alkyl, R,- phenyl, R -phenyl-lower alkyl, R is lower alkyl, R,- phenyl, R,-phenyl-lower alkyl, and X is hydrogen. hydroxy, lower alkanoyloxy, R,phenylCO-O, R,- phenyl-lower alkanoyloxy, lower alkylamine, dibenzylamine, N,N'-dibenzylpyridinium, pyridinium, lquinolinium. l-picolinium or together X and R represent a bond linking carbon and oxygen in a lactone alkoxy, hydrox or carboxy.

is lower alkyl.

4. A compound as in claim 2 wherein R and R each is alkali metal ion.

5. A compound as in claim 2 wherein R is hydrogen and R is lower alkyl.

6. A compound as in claim 1 wherein R is potassium, R, is phenyl. R is ethyl and X is hydrogen. 7 7. The alkali metal salt of the compound of claim I 45 wherein R, is phenyl and X is hydrogen.

-CH O -R I R, is phenyl, thienyl, furyl, oxazolyl, isoxazolyl or thiazolyl; R and R each is lower alkyl, and X is hydrogen or acetoxy. 

1. A COMPOUND OF THE FORMULA
 2. A compound as in claim 1 wherein R1 is phenyl.
 3. A compound as in claim 2 wherein R and R2 each is lower alkyl.
 4. A compound as in claim 2 wherein R and R2 each is alkali metal ion.
 5. A compound as in claim 2 wherein R is hydrogen and R2 is lower alkyl.
 6. A compound as in claim 1 wherein R is potassium, R1 is phenyl, R2 is ethyl and X is hydrogen.
 7. The alkali metal salt of the compound of claim 1 wherein R1 is phenyl and X is hydrogen.
 8. A compound as in claim 1 wherein R is potassium, R1 is phenyl, R2 is ethyl and X is acetoxy.
 9. A compound as in claim 2 wherein R is alkali metal, R2 is lower alkyl and X is lower alkanoyloxy.
 10. A compound as in claim 2 wherein R is alkali metal, R2 is lower alkyl and X is hydrogen.
 11. A compound as in claim 1 wherein R is hydrogen, lower alkyl, alkali metal, trimethylsilyl or 